The mutational patterns that are described in these case reports have several key commonalities with the variants of concern and variants of interest that have become widespread. The variants B.1.1.7, B.1.351, and P.1 have at least three times as many mutations as the viruses that were circulating when these variants emerged. Likewise, investigators have detected 45 substitutions and deletions (including 17 in the spike protein) in B.1.617.2 as compared with B.1.1.7, the variant that was prevalent when B.1.617.2 emerged. A high percentage of these polymorphisms (>40%) are in the spike protein, which constitutes only 13% of the proteome. Because the spike protein is the prime target of the protective antibody response and mediates viral entry, a preponderance of mutations in this protein is consistent with adaptive evolution.
In addition, selection pressure is also shown by evidence of convergent evolution. Convergent mutations are seen in variants of concern and interest and in sequences obtained from immunocompromised patients, in particular deletions in the N terminal domain (NTD) (69-70del, Y144del, and 157-158del), the NTD supersite, and the receptor-binding domain (RBD) (K417N and E484K). These domains were associated with antibody escape or mutations that were probably associated with increased transmissibility (N501Y9 and P681H/R) ().10 Such convergent mutations have been reported in both immunocompetent and immunosuppressed populations.11 The selective advantage of these convergent mutational alterations is supported by the pace at which these variants, particularly B.1.1.7, displaced previously circulating viruses. The evolutionary pattern of the B.1.1.7 variant in the United Kingdom illustrates the rapid evolution of multiple mutations in the spike protein and its subsequent rapid spread throughout the populace (). The succession of new variants of concern or interest and the emergence of sublineages in these variants (i.e., variants of variants) illustrate a shifting evolutionary landscape in which new variants can rapidly become dominant, as suggested by the recent swift dissemination of B.1.617.2 that was originally identified in India.12 This variant shows a constellation of mutations that were identified in previous variants of concern or interest.
These compilations of case reports indicate the need to identify whether certain forms of immunosuppression are associated with an increased risk of such multimutational escape patterns — for instance, specific cancers or specific therapies, such as the development of B-cell aplasia related to CAR T-cell or anti-CD20 therapy, prolonged use of glucocorticoids, long-term chemotherapy, or radiotherapy. Similarly, organ transplant recipients and those with untreated or poorly controlled human immunodeficiency virus infection may also have prolonged SARS-CoV-2 infection and could constitute a reservoir of divergent escape variants that can spread in the general community. Prolonged viral replication in the context of an inadequate immune response facilitates the emergence of immune-pressure escape mutations.